Org. Synth.2002,79, 244
DOI: 10.15227/orgsyn.079.0244
4-METHOXYCARBONYL-2-METHYL-1,3-OXAZOLE
[4-Oxazolecarboxylic acid, 2-methyl-, methyl ester]
Submitted by James D. White, Christian L. Kranemann, and Punlop Kuntiyong
1.
Checked by Mitsuru Kitamura and Koichi Narasaka.
1. Procedure
A.Methyl α-[(methoxyethylidene)amino]acetate (1). Aflame-dried,500-mL, two-necked, round-bottomed flask is equipped with astirbar,rubber septum, and anargon inlet.The flask is charged withmethyl acetimidate hydrochloride(10.0 g, 91 mmol)(Note 1)anddrydichloromethane (140mL)(Note 2). The stirred suspension is cooledto 0°C and solidmethyl glycinate hydrochloride(11.5 g, 91 mmol, Note1)is added in one portion with apowder funnel under a streamof Ar. After the mixture is stirred for 45 min at 0°C, a solution ofdrytriethylamine (12.7 mL, 91mmol)(Note 2) indrydichloromethane (11 mL) is addedviasyringe pump during 2.5 hr. Stirring is continued for 5hr while the mixture is allowed to warm slowly to room temperature(Note 3).Water (30 mL, pH 7 buffered) is added, giving a clear biphasic mixture(Note 4).The phases are separated in a250-mL separatory funnel, andthe aqueous phase is extracted withdichloromethane(2 × 15 mL). The combined organic phases are washedwith pH 7 buffered water (1 × 17 mL) andbrine (1× 17 mL). After the organic solution is dried overanhydrousmagnesium sulfate, it isfiltered and concentrated under reduced pressure, leaving11.50 g of the crude product as a colorless solid. Distillationof this material (41 mm, 135°C) gives10.10g (76%) of puremethyl α-[(methoxyethylidene)amino]acetate(1, Note5).
B.Potassiummethyl α-[(methoxyethylidene)amino]-β-hydroxyacrylate (2). Aflame-dried,2-L, three-necked, round-bottomed flask is equipped with astirbar,rubber septum, and anargon inlet.The flask is charged with a solution ofpotassiumtert-butoxide(7.81 g, 70 mmol)(Note 1)indrytetrahydrofuran (THF, 200mL)(Note 2), and the solution is stirredat −10°C for 15 min. A solution ofmethylα-[(methoxyethylidene)amino]acetate (10.10 g, 70mmol) andmethyl formate (5.0 mL,84 mmol)(Note 1) indryTHF (50 mL) is added via asyringe pumpduring 20 min. After a further 5 min at −10°C,drydiethyl ether (750 mL)(Note 2)is added via acannula, resulting in the formation of a yellowishprecipitate. Stirring is continued for 2 hr at 0°C and the cold solution is filteredthrough aSchlenk tube(Note 6) underargon. The pale yellow filter cake is washed underargonwithdrydiethyl ether (3 ×40 mL), and the cake is dried under anargonstream and then under reduced pressure. The solid is transferred from theSchlenktube to awide mouthed vessel under anargonatmosphere. The resultant crudepotassiummethyl α-[(methoxyethylidene)amino-β-hydroxyacrylate(2) is used directly for the next step(Note 7).
C.4-Methoxycarbonyl-2-methyl-1,3-oxazole(3). Aflame-dried, 50-mL, two-necked, round-bottomed flaskis equipped with astir bar,reflux condenser,rubber septum, and anargon inlet. Theflask is charged withglacialacetic acid(15 mL) which is heated to reflux. To this is added crudepotassium methyl α-[(methoxyethylidene)-amino]-β-hydroxyacrylate,prepared above, in one portion with apowder funnel. Materialwhich adheres to the wall of the funnel and the flask is washed into the mixture witha stream ofacetic anhydride.The mixture is stirred at reflux for 1.5 hr, then allowed to cool and carefully pouredinto a250-mL Erlenmeyer flask containing a saturatedaqueous solution ofsodium bicarbonate (50mL)(Note 7). The pH of the solution is adjustedto 8 by further addition of solidsodium bicarbonate(Note 8). The solution is extracted withdichloromethane(4 × 30 mL), and the organic extract is dried overanhydroussodium sulfate,filtered and concentrated under reduced pressure to give4.48 g of crude product. This is purified by distillation(41 mm, 150°C) to afford3.74 g(38% from 1; Note9) of4-methoxycarbonyl-2-methyl-1,3-oxazole(3, Note10).
2. Notes
1.
Methyl acetimidate hydrochloride,methyl glycinate hydrochloride,potassium tert-butoxide,andmethyl formate were purchased from Aldrich ChemicalCompany, Inc., and were used without further purification. Thecheckers purchased
methyl glycinate hydrochloridefrom Tokyo Chemical Industry Co. and
potassiumtert-butoxide andmethyl formate from KantoChemical Co. Step A is very sensitive to moisture.
Ethylacetimidate hydrochloride is very hygroscopic. It must be dried beforeuse in a
desiccator over
phosphoruspentoxide (P2O5) under reduced pressureand handled under argon.
2.
Dichloromethaneand
triethylamine were freshlydistilled from
calcium hydrideunder
argon before use.
THF anddiethylether were distilled from
sodiumand
benzophenone under
argon.The checkers used
THF anddiethyl etheras received from Kanto Chemical Co. (reagent grade,<0.005% water).
3. After 2 hr the
ice-bath is no longer refilledwith fresh ice, allowing the mixture to warm to room temperature during the remaining3 hr.
4. Stirring for 2 to 3 min is required for complete dissolution ofall precipitate.
5. The product is characterized by NMR spectroscopy:
1H NMR (400 MHz, CDCl
3) δ:1.86 (s, 3 H), 3.66 (s, 3 H), 3.71 (s, 3 H),4.03 (s, 2 H);
13CNMR (100 MHz, CDCl
3) δ: 14.5, 50.6, 51.4,52.2, 164.8, 171.1.
6. Compound
2 is very hygroscopic.
1H NMR (500 MHz, DMSO-d
6) δ:1.60 (s, 3 H), 3.36 (s, 3 H), 3.49 (s, 3 H),8.57 (s, 1 H).
7.
Caution: a large amount ofcarbon dioxideis liberated!8. Water (50 mL) is added to keep all inorganic salts dissolved.
9. The submitters found that the yield of
3 can be increasedto
58% if crude
2, obtainedin step B by rotary evaporation of the solvent (rather than filtration through a
Schlenktube followed by washing with
ether),is taken directly into hot
glacialacetic acidin step C. This procedure minimizes exposure of hygroscopic
2 to moisture.These changes were not checked.
10. The product is characterized by NMR-spectroscopy:
1H NMR (400 MHz, (CDCl
3) δ:2.31 (s, 3 H), 3.70 (s, 3 H), 7.97 (s, 1 H);
13C NMR (100MHz, CDCl
3) δ: 13.5, 51.8, 133.0,143.6, 161.4, 162.2.
3. Discussion
The method described for the preparation of
4-methoxycarbonyl-2-methyl-1,3-oxazoleis that of Cornforth,
2 and is widelyapplicable to the synthesis of 2-substituted 1,3-oxazole-4-carboxylates.
3 Theappropriate imidate hydrochloride required for step A is obtained from the reactionof a nitrile with an alcohol in the presence of
hydrochloricacid (eq. 1).
4 A differentsynthesis of 2-substituted 1,3-oxazole-4-carboxylates employing
rhodium-catalyzedheterocycloaddition of a diazomalonate to a nitrile has been described in
OrganicSyntheses by Helquist,
5 butappears to be less general than the present route.
New methods for the synthesis of 2,4-disubstitued oxazoles are summarized in arecent review.
6 2-Alkyl-1,3-oxazoles bearing alkyl, aryl, or acylsubstitution at C4 are common substructures in natural products.
7 Examplesinclude macrolides such as
rhizoxin(4),
8hennoxazole A(5),
9 and
phorboxazoleA (6),
10as well as many cyclic peptides that incorporate an oxazole subunit presumably derivedfrom serine.
114-Methoxycarbonyl-2-methyl-1,3-oxazole(3) is metalated exclusively at C5 with
n-butyllithium.
3 Selective functionalization at the methyl group of
3 canbe achieved with
N-bromosuccinimideto yield the 2-bromomethyl derivative
8. The latter affords a route to 2,4-disubstitutedoxazoles that are not immediately accessible through the Cornforth synthesis. Thus,
8 undergoes displacement with
sodium phenylsulfinateto give sulfone
9, which can then be transformed to aldehyde
10.
References and Notes
- Department of Chemistry, Oregon StateUniversity, Corvallis, OR 97331-4003.
- Cornforth, J. W.; Cornforth,R. H.J. Chem. Soc.1947, 96.
- Meyers, A. I.; Lawson, J. P.; Walker, D. G.; Lindermann, R.J.J. Org. Chem.1986,51, 5111.
- (a) Molina, P.;Lopez-Leonardo, C.; Llamas-Botia, J.; Foces-Foces, C.; Llamas-Sais, A. L.Synthesis1995, 449; (b) Law, H.; Dukat, M.; Teitler, M.; Lee,D. K. H.; Mazzocco, L.; Kamboj, R.; Rampersad, V.; Prisinzano, T.; Glennon, R. A.J. Med. Chem.1998,41, 2243.
- Tullis, J. S.; Helquist,P.Org. Synth., Coll. Vol. IX1998, 155.
- Gilchrist, T. L.J. Chem. Soc., PerkinTrans. 11998, 615. A comprehensive listing of citations tooxazole chemistry, including synthesis, is contained in reference5.
- (a)Lewis, J. R.Nat. Prod. Rep.1998,15, 371, 417;(b) Roy, R. S.; Gehring, A. M.; Milne, J. C.; Belshaw, P. J.; Walsh, C.T.Nat. Prod. Rep.1999,16, 249.
- Iwasaki, S.; Namikoshi, M.;Kobayashi, H.; Furukawa, J.; Okuda, S.Chem. Pharm. Bull.1986,34,1387.
- Ichiba, T.; Yoshida, W. Y.;Scheuer, P. J.; Higa, T.; Gravalos, D. G.J. Am. Chem. Soc.1991,113,3173.
- Searle, P. A.;Molinski, T. F.J. Am. Chem. Soc.1995,117, 8126.
- Lewis, J. R.Nat. Prod. Rep.1999,16, 389.
Appendix
Chemical Abstracts Nomenclature (Collective Index Number);
(Registry Number)
4-Methoxycarbonyl-2-methyl-1,3-oxazole:
4-Oxazolecarboxylicacid, 2-methyl-, methyl ester (11); (85806-67-3)
Methyl α-[(methoxyethylidene)amino]acetate:
Glycine,N-(1-methoxyethylidene)-, methyl ester (10); (64991-38-4)
Methyl acetimidate hydrochloride:
Acetimidicacid, methyl ester, hydrochloride (8);
Ethanimidic acid, methylester, hydrochloride (9); (14777-27-6)
Methyl glycinate hydrochloride: ALDRICH:
Glycinemethyl ester hydrochloride:
Glycine, methyl ester, hydrochloride(8,9); (5680-79-5)
Triethylamine (8);
Ethanamine, N,N-diethyl-(9); (121-44-8)
Potassium methyl α-[(methoxyethylidene)amino]-β-hydroxyacrylate:
Propanoic acid, 2-[(1-methoxyethylidene)amino]-3-oxo-, methyl ester, ion(1−),potassium (11); (105205-36-5)
Potassium tert-butoxide:
tert-Butyl alcohol,potassium salt (8);
2-Propanol, 2-methyl-, potassium salt(9); (865-47-4)
Methyl formate:
Formic acid, methyl ester(8,9); (107-31-3)
Acetic acid (8,9); (64-19-7)
Acetic anhydride (8);
Acetic acid, anhydride(9); (108-24-7)
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